Our limited knowledge of the mechanisms underlying PD demands the clevelopment of innovative avenues of investigation. The extensive characterization of the budding yeast Saccharomyces cerevisiae and the many tools developed for its manipulation makes it a powerful system for studying complex biological problems. Alpha-synuclein (aS), one of the established key players in PD, will be the focus of our Study. Preliminary data suggest that many of the basic features of aS biology in mammalian neurons is recapitulated in yeast. The proposed studies should generate a wealth of pilot information pertaining both to normal aS biology and potential therapeutic strategies to synergize with studies in other systems. We will combine our own expertise in yeast genetics and cell biology with the expertise of a group of investigators, ranging from biochemists, to geneticists and neurobiologists.